TY - JOUR
T1 - YAP promotes global mRNA translation to fuel oncogenic growth despite starvation
AU - Hwang, Daehee
AU - Baek, Seonguk
AU - Chang, Jeeyoon
AU - Seol, Taejun
AU - Ku, Bomin
AU - Ha, Hongseok
AU - Lee, Hyeonji
AU - Cho, Suhyeon
AU - Roh, Tae Young
AU - Kim, Yoon Ki
AU - Lim, Dae Sik
N1 - Publisher Copyright:
© The Author(s) 2024.
PY - 2024/10
Y1 - 2024/10
N2 - Yes-associated protein (YAP) and transcriptional co-activator with PDZ-binding motif (TAZ) play fundamental roles in stem/progenitor cell expansion during homeostasis, and their dysregulation often leads to tissue overgrowth. Here, we show that YAP activation is sufficient to overcome the restriction of global protein synthesis induced by serum starvation, enabling cells to sustain proliferation and survival despite an unfavorable environment. Mechanistically, YAP/TAZ selectively promoted the mTORC1-dependent translation of mRNAs containing 5′ terminal oligopyrimidine (5′TOP) motifs, ultimately increasing the cellular polysome content. Interestingly, DNA damage-inducible transcript 4 (DDIT4), a negative regulator of mTORC1, was upregulated by serum starvation but repressed by YAP/TAZ. DDIT4 was sufficient to suppress the translation and transformative potential of uveal melanoma cells, which are often serum unresponsive due to G protein mutations. Our findings reveal a vital role for protein synthesis as a key modality of YAP/TAZ-induced oncogenic transformation and indicate the potential for targeting mTORC1 or translation to treat YAP/TAZ-driven malignancies.
AB - Yes-associated protein (YAP) and transcriptional co-activator with PDZ-binding motif (TAZ) play fundamental roles in stem/progenitor cell expansion during homeostasis, and their dysregulation often leads to tissue overgrowth. Here, we show that YAP activation is sufficient to overcome the restriction of global protein synthesis induced by serum starvation, enabling cells to sustain proliferation and survival despite an unfavorable environment. Mechanistically, YAP/TAZ selectively promoted the mTORC1-dependent translation of mRNAs containing 5′ terminal oligopyrimidine (5′TOP) motifs, ultimately increasing the cellular polysome content. Interestingly, DNA damage-inducible transcript 4 (DDIT4), a negative regulator of mTORC1, was upregulated by serum starvation but repressed by YAP/TAZ. DDIT4 was sufficient to suppress the translation and transformative potential of uveal melanoma cells, which are often serum unresponsive due to G protein mutations. Our findings reveal a vital role for protein synthesis as a key modality of YAP/TAZ-induced oncogenic transformation and indicate the potential for targeting mTORC1 or translation to treat YAP/TAZ-driven malignancies.
UR - http://www.scopus.com/inward/record.url?scp=85205375920&partnerID=8YFLogxK
U2 - 10.1038/s12276-024-01316-w
DO - 10.1038/s12276-024-01316-w
M3 - Article
C2 - 39349825
AN - SCOPUS:85205375920
SN - 1226-3613
VL - 56
SP - 2202
EP - 2215
JO - Experimental and Molecular Medicine
JF - Experimental and Molecular Medicine
IS - 10
ER -